Project Summary Each year, up to 40% of adolescents witness or experience an assault in their community. The stress of such exposures to violence (EtV) greatly increases the probability of initiating use of illicit drugs as well as becoming addicted to them. This proposal tests the hypothesis that the stress of EtV recalibrates the neural processes underlying emotional reactivity and regulation, which leads to changes in affect reactivity, risk-taking, and working memory. These psychological changes, either independently or in concert, lead to increased risk for the initiation and escalation of substance use. We also hypothesize that the degree to which EtV elicits these changes in brain and behavior is highly dependent on the environmental context in which EtV occurs and therefore moderated by community level factors (e.g. collective efficacy; neighborhood economic disadvantage) as well as more traditionally measured psychological factors. To test this multi-system model of EtV's effects on substance use, we will recruit from our ongoing, longitudinal developmental study of 1500 adolescents in Franklin County, OH, a subsample (n=600) that will continue (at years 2 and 5; 4 total time points) these ecological momentary assessment (EMA), global positioning (GPS), and interview assessments of spatial exposures to EtV and substance use (including objective head hair measures). At 2 additional time points (years 1 and 4), youths will complete a comprehensive neuroimaging battery that includes measurements of brain structure, resting state activity, and neural activity during 4 well-validated neurocognitive tasks that probe the processes hypothesized to be affected by EtV and associated with increased risk for substance use: (1) risk-taking behavior; (2) reward sensitivity; (3) threat reactivity; and (4) working memory. In support of our theory linking EtV to substance use, each of these tasks has been shown to be impacted by stressful experiences like EtV as well as altered by regular substance use. Targeted recruitment from the parent study will enhance the proportion of youths who have already used illicit substances as well as experienced EtV. Aim 1 determines the independent effects of EtV and substance use on longitudinal changes in neural structure and function as well as cross-sectional differences. Aim 2 determines the degree to which neural activity predicts future substance use. Aim 3 evaluates the degree to which community resilience and risk factors moderate these changes in neural function and structure. Example moderators include neighborhood and activity space exposures (e.g. collective efficacy, violence levels), family social processes and resources (e.g. parental monitoring, poverty), and life history (early childhood adversity) factors. With a longitudinal design, we will be able to determine the temporal ordering of how these risk and resilience factors modify the trajectory of neural changes resulting from EtV, which will provide new understanding of how these variables influence substance abuse risk and suggest targets for intervention at the community, psychological, or neural level that might prevent or attenuate the enduring effects of EtV.